Activated innate immunity and inflammation mediate the pathogenesis of many diseases. New perspectives on the contribution of innate immunity to these diseases, can lead to important new therapeutic considerations and goals for treatment. The overall goal of our research plan is to define immunological mechanisms, aberrant or otherwise, which could be responsible for exacerbation of inflammatory diseases in general. Here we propose to use a model of aggressive periodontal disease (AgP) in which aberrant inflammatory processes are evident. Aggressive periodontitis is a rare, severe and rapidly progressing form of periodontitis usually following a simple pattern of familial transmission with a mean prevalence in the world around 2%3-5. Because the prevalence of aggressive periodontal disease is so low, data about mechanisms of this disease is very scarce and results are based mostly on clinical experience of individual clinicians rather than controlled studies. Interestingly, we have identified a cohort of 47 African-American children in an underserved region of Tallahassee, all within one single health department in Leon County, diagnosed with moderate to severe localized AgP. An important strength of this application is the similarity of the cohort in terms of race, age and pattern of disease coupled with the rarity of the disease and availability of related and unrelated healthy controls. We hypothesize that this cohort harbors aberrant regulation of immunological responses to bacterial pathogens which leads to increased severity and timing of periodontal destruction. Here we propose to investigate regulatory mechanisms of cyto/chemokine expression which directly and indirectly contribute to tissue destruction and periodontal disease progression. The `hyper-responsive'phenotype refers to an increased inflammatory response by the innate immune system, therefore, one objective of this proposal seeks to determine if this underlying defect in the immune response is present in the Tallahassee cohort and if this trait can be elicited in response to periodontal pathogens. Micro RNA (miRNA) regulate pro-inflammatory cytokine mRNA and are up regulated upon LPS stimulation. It is plausible that miRNA regulate cytokine gene expression during periodontal disease in response to LPS stimulation by oral pathogens. Therefore, an additional objective of this proposal is to determine if aberrant expression of miRNA result in dysregulation of cyto/chemokine expression resulting in more aggressive disease progression. Importantly, these data will allow us to contribute greatly to the field of immune regulation, and will spawn multiple research projects in this ever evolving field. PUBLIC HEALTH RELEVANCE: The immune system is responsible for defending us from multiple types of insult, yet an over-active immune system plays a large role in many disease processes. Therefore, it is the goal of this proposal and our research plan to investigate regulation of the immune response in a model of aggressive periodontal disease in which over-active immune processes are evident and play a significant role in disease progression. Regulation mechanisms deciphered here will be translated to other disease processes which incorporate over-active immune responses.